Macrophage ATP citrate lyase aggravates acetaminophen-induced acute liver injury via TWEAK/FN14 signaling in mice

Hepatic damage and inflammatory responses are common adverse outcomes triggered by exposure to diverse toxicants. Among drug-induced liver pathologies, acetaminophen (APAP)-mediated hepatotoxicity stands as a leading etiology of acute liver failure in Western populations, yet the involvement of macrophage ATP-citrate lyase (ACLY) in this process remains insufficiently characterized. This research clarifies the mechanistic contributions of macrophage ACLY to APAP-induced acute liver injury through integrated in vivo and in vitro approaches. Genetic ablation of macrophage ACLY markedly attenuated hepatic necrosis, improved survival outcomes in male murine models following APAP treatment, and substantially reduced biochemical markers of injury (plasma ALT/AST) and pro-inflammatory cytokine levels. Transcriptomic profiling identified diminished FN14 expression within cytokine-cytokine receptor interaction signaling pathways in ACLY-deficient macrophages following APAP challenge. In vitro analyses demonstrated that ACLY depletion suppressed LPS-induced M1 macrophage polarization and TWEAK secretion. Mechanistically, TWEAK released from macrophages activates hepatocyte FN14 receptors, initiating oxidative stress cascades and mitochondrial dysfunction that culminate in hepatocellular damage. Our findings establish macrophage ACLY as a pivotal regulator of APAP hepatotoxicity mediated through the TWEAK/FN14 axis, thereby proposing novel therapeutic targets for acute liver injury management.